Process for manufacture of telmisartan

ABSTRACT

A process for preparing telmisartan by reacting 2-n-propyl-4-methyl-6-(1′-methylbenzimidazol-2′-yl)benzimidazole with a compound of formula (IV) 
     
       
         
         
             
             
         
       
     
     wherein Z is a leaving group, to obtain the compound 2-cyano-4′-[2″-n-propyl-4″-methyl-6″-(1′″-methylbenzimidazol-2′″-yl)benzimidazol-1″-ylmethyl]biphenyl, and subsequently hydrolyzing the nitrile function to obtain the acid function.

RELATED APPLICATIONS

This application claims benefit of U.S. Ser. No. 60/465,952, filed Apr.28, 2003, and claims priority to German Application No. 103 14 702.0,filed Mar. 31, 2003, each of which is hereby incorporated by referencein its entirety.

FIELD OF THE INVENTION

The present invention relates to a new process for preparing4′-[2-n-propyl-4-methyl-6-(1-methylbenzimidazol-2-yl)benzimidazol-1-ylmethyl]biphenyl-2-carboxylicacid (INN: telmisartan).

BACKGROUND OF THE INVENTION

Telmisartan is an angiotensin II receptor antagonist which is suitablefor the treatment of high blood pressure and other medical indicationsas described in EP 502314 B 1. The active substance has the followingstructure:

Telmisartan is generally prepared and sold in the form of the free acid.As disclosed in WO 00/43370, crystalline telmisartan occurs in twopolymorphic forms which have different melting points. Under theinfluence of heat and moisture, the lower-melting polymorphic form Bchanges irreversibly into the higher-melting polymorphic form A.

Hitherto, telmisartan has been synthesized industrially by reacting2-n-propyl-4-methyl-6-(1′-methylbenzimidazol-2′-yl)benzimidazole (I)with tert-butyl 4′-bromomethylbiphenyl-2-carboxylate (H) andsubsequently saponifying according to the following Diagram 1.

The coupling by nucleophilic substitution in the first reaction step isdescribed in general terms in EP 502314 B1 as process b), while thesaponification of the tert-butyl ester group on a laboratory scale usingtrifluoromethylacetic acid is described in the patent specification asExample 1. Industrially, saponification has up till now been carried outwith concentrated aqueous hydrobromic acid. Scaling up the method ofsynthesis known from the patent specification to a large-scaleindustrial process was surprisingly beset with problems. Thus, theactive substance prepared by the process known up till now can only beobtained in a satisfactory quality after running through a number ofprocess steps (the crude product does not have the required purity untilit has been recrystallized twice), while very long centrifuging anddrying times are needed when isolating the substance. The telmisartansynthesized on an industrial scale according to Diagram 1 is obtainedafter working up in the form of a product which has to be subjected to asecond crystallization step to complete the purification. In thecrystallization step, which is absolutely essential, the morphology ofthe end product crystallizing out led to unforeseen problems.

The product precipitated in the form of long needles is difficult tofilter, wash, and isolate and, because of the inclusion of solvent, isalso characterized by a very long drying time and forms large, very hardlumps during the drying process. Grinding up these lumps results in adry powder which has a strong tendency to electrostatic charging and isvirtually impossible to pour.

The abovementioned undesirable properties of a product have alwaysproved to be a major obstacle to the large-scale production of acompound as they stop the product being manufactured reproducibly inlarge quantities and allow a high degree of purity to be achieved onlywith considerable difficulty or at additional high technical costs.

The aim of the present invention is therefore to provide an alternativemethod of preparing telmisartan, which can be used on a large scale andallows telmisartan to be easily worked up, purified, and isolatedwithout the disadvantages mentioned above.

BRIEF SUMMARY OF THE INVENTION

Surprisingly it has been found that from a technical point of view thereaction of2-n-propyl-4-methyl-6-(1′-methylbenzimidazol-2′-yl)benzimidazole

with a compound of general formula (IV)

wherein Z denotes a leaving group such as a halogen atom, for example, achlorine, bromine, or iodine atom, or a substituted sulfonyloxy group,for example, a methanesulfonyloxy, phenylsulfonyloxy, orp-toluenesulfonyloxy group, to obtain the compound2-cyano-4′-[2″-n-propyl-4″-methyl-6″-(1′″-methylbenzimidazol-2′″-yl)benzimidazol-1″-ylmethyl]biphenyl(V)

which may, if desired, be subjected to working up (Step (a)), andsubsequent hydrolysis of the nitrile to the acid function (Step (b))and, if desired, conversion of the compound (V) during working up intothe hydrochloride, has considerable advantages over the synthesis shownin Diagram 1, and in particular does not have the drawbacks mentionedabove for large-scale production by the conventional method.

DETAILED DESCRIPTION OF THE INVENTION Step (a)

The reaction of the compound (I) with a compound of general formula(IV), wherein Z preferably denotes a halogen atom, particularly thebromine atom, is conveniently carried out in a solvent or mixture ofsolvents such as methylene chloride, diethyl ether, tetrahydrofuran,dioxane, dimethylsulfoxide, dimethylformamide, dimethylacetamide,dimethylformamide/tert-butanol, dimethylacetamide/tert-butanol, toluene,and benzene, optionally in the presence of an acid-binding agent such assodium carbonate, potassium carbonate, sodium hydroxide, potassiumhydroxide, sodium methoxide, potassium methoxide, potassiumtert-pentoxide, potassium tert-butoxide, potassium n-butoxide, sodiumhydride, triethylamine, or pyridine, while the latter two may also beused as solvents, for example, at a temperature between 0° C. and 100°C. The base is preferably used in powdered form if it is a solid.

Preferably, the reaction of the compound (I) with a compound of generalformula (IV) is carried out in a solvent or mixture of solvents selectedfrom dimethylsulfoxide, dimethylformamide, dimethylacetamide,dimethylformamide/tert-butanol, and dimethylacetamide/tert-butanol inthe presence of sodium hydroxide, potassium hydroxide, or potassiumtert-butoxide at a temperature between 0° C. and 30° C.

Particularly preferably, the reaction of the compound (I) with acompound of general formula (IV) is carried out in dimethylacetamide ordimethylacetamide/tert-butanol in the presence of potassium hydroxide ata temperature between 0° C. and 20° C.

Working Up

After the reaction has ended, the solvent is removed, for example,distilled off in a water-jet vacuum, and the residue is treated with asolvent in which the nitrile (V) has only limited solubility or ismoderately soluble in the heat, for example, with an alcohol such asmethanol, ethanol, n-propanol, isopropanol, n-butanol or isobutanol,with an aromatic hydrocarbon such as benzene or toluene, with anethereal solvent such as diethyl ether, tetrahydrofuran, dioxane, ortert-butylmethylether, the ethereal solvents and particularlytert-butylmethylether being preferred, or with water. The crystals,which may be precipitated after cooling to 10° C. to 20° C., are suctionfiltered and washed first with the solvent used and then with water. Ifnecessary, the product is dried at elevated temperature, for example at50° C. to 100° C., in a vacuum drying cupboard. The nitrile (V) isgenerally obtained in excellent yields between 80% and 90% of theory andwith excellent quality (purity according to HPLC >99.5%).

Step (b)

The subsequent hydrolysis of the nitrile function into a carboxy groupis conveniently carried out in water, in an organic solvent, or in amixture of an organic solvent with water, while the organic solvent maybe, for example, methanol, ethanol, n-propanol, isopropanol,tetrahydrofuran, dioxane, ethylene glycol, propylene glycol, diglyme,dimethylsulfoxide, or diethylene glycol monomethyl ether, in thepresence of an acid such as trifluoroacetic acid, trichloroacetic acid,hydrochloric acid, sulfuric acid, or phosphoric acid or in the presenceof a base such as lithium hydroxide, sodium hydroxide, potassiumhydroxide, cesium hydroxide, or calcium hydroxide or the anhydridesthereof; at temperatures between 80° C. and 200° C., while the waterneeded for the reaction may also be a constituent of one of the reagentsused, e.g., one of the abovementioned aqueous acids, or may be generatedunder the reaction conditions from the reagents, possibly from one ofthe abovementioned alkali metal hydroxides.

Preferably, the hydrolysis of the nitrile function is carried out in ahigh-boiling solvent system selected from ethylene glycol/water andpropylene glycol/water, in the presence of a base, potassium hydroxidebeing particularly suitable, at temperatures between 140° C. and 200°C., particularly at a temperature between 155° C. and 185° C.

Working Up

After the reaction has ended, the solvent is removed, for example,distilled off in a water-jet vacuum, the residue is diluted with waterand taken up in hydrochloric acid, for example, with 5% to approximately32% concentrated hydrochloric acid, preferably with 5% to 20%hydrochloric acid, whereupon telmisartan hydrochloride crystallizes out.The crystal suspension is cooled to 10° C. to 25° C. if necessary andmay be stirred at this temperature for a certain length of time, forexample up to 3 hours. After the crystals have been suction filtered,they are washed with water and if necessary dried in a vacuum dryingcupboard at elevated temperature, for example, at 50° C. to 120° C.

Telmisartan in acid form can be liberated from the telmisartanhydrochloride in the usual way, e.g., by titration with aqueous alkalimetal hydroxide solution. For example, the acid form is liberatedanalogously to the method described in WO 0043370 (page 3, line 6, topage 4, line 38, and Examples 1 to 3).

For large-scale production the process according to the invention hasthe following advantages inter alia deserving special mention:

-   -   compounds of formula (IV), particularly        4′-bromomethyl-2-cyanobiphenyl, are mass produced and may be        obtained cheaply;    -   the coupling of components (I) and (IV) according to Step (a)        may be carried out in a high concentration and at a        correspondingly high throughput, while working up particularly        using tert-butylmethylether yields the nitrile (V) as a        precipitate which is easy to filter and wash, thus dispensing        with the need for additional laborious working up procedures;    -   the nitrile (V) is obtained in excellent yields of between 80%        and 90% of theory and with excellent quality (purity according        to HPLC >99.5%);    -   the saponification of the nitrile (V) in Step (b) also produces        excellent yields >95% of theory; and    -   the end product telmisartan may be isolated either as an        ampholyte or, preferably, by precipitation with hydrochloric        acid as a hydrochloride which is easy to filter and hence easy        to purify.

The following procedure is used, in a particularly preferred manneraccording to the invention:

Step (a):

All the quantities specified relate to a batch size of 0.1 mol of thecompound (I) and if the batch size is altered must be multiplied by acorresponding factor.

50 mL to 200 mL, preferably 80 mL to 120 mL, of solvent per 0.1 mol ofthe compound (I) is placed in a suitably dimensioned reaction vessel,the compound (I) is suspended in the solvent and 0.1 mol to 0.2 mol ofbase, preferably 0.102 mol to 0.12 mol, are added batchwise thereto withstirring, while the temperature is maintained at between 10° C. and 50°C., preferably 15° C. to 30° C., and when the exothermic reaction hasended stirring may be continued for up to another 3 hours at thistemperature. The mixture is cooled to approximately 0° C. to 10° C., forexample, approximately 5° C., and then a mixture of 0.1 mol to 0.2 molof a compound of general formula (IV), preferably 0.100 mol to 0.12 mol,with 50 mL to 200 mL solvent (per 0.1 mol of the compound (IV)) is addeddropwise at 10° C. to 30° C., preferably at approximately 20° C. Thereaction mixture is optionally maintained at approximately 0° C. to 20°C., preferably 5° C. to 10° C., by cooling with the ice bath. Then itmay be rinsed out with a few mL of solvent and stirred for up to another3 hours at 0° C. to 20° C.

In another embodiment the base is placed in 30 mL to 100 mL of solvent,preferably dimethylformamide, dimethylacetamide,dimethylformamide/tert-butanol, or dimethylacetamide/tert-butanol, at10° C. to 30° C., stirred for up to an hour at about 20° C., forexample, and then a suspension of the compound (I) in 30 mL to 100 mLsolvent is slowly metered in at this temperature. All the other stepsare the same as in the previous embodiment. The solvent mixturesspecified are used in a ratio by volume of amide to tert-butanol is 10:1to 2.5:1, for example, 5:1.

Working Up

The solvent is conveniently largely distilled off under reducedpressure, for example, under a water-jet vacuum, whereupon the productcrystallizes out. After the residue has cooled to approximately 40° C.to 80° C., preferably about 60° C., it is diluted with 100 mL to 300 mLof solvent (per 0.1 mol batch size, based on compound (I)), preferablytert-butylmethylether, and stirred for up to 5 hours without any inputof energy. The mixture is cooled to 0° C. to 30° C., preferably 15° C.to 20° C., and stirred for up to a further 5 hours at this temperature.The crystals are suction filtered and washed batchwise with 50 mL to 150mL of the solvent and then with 200 mL to 300 mL of water. The productis dried in the vacuum drying cupboard at 50° C. to 100° C., preferablyabout 60° C.

Step (b):

Unless otherwise stated, all the amounts specified are based on a batchsize of 0.05 mol of the compound (V) and must be multiplied by acorresponding factor if the batch size is altered.

0.05 mol of the compound (V), 200 mL to 300 mL of the organic solvent,0.5 mL to 5 mL of water and 0.3 mol to 0.5 mol of the base are combinedand heated to the boiling temperature of the solvent system used, i.e.,if the preferred ethylene glycol/water mixture is used, it is heated to140° C. to 200° C., preferably to 155° C. to 185° C. The mixture isstirred for up to 24 hours at this temperature.

In another embodiment, 0.361 mol of the nitrile (V) are placed in 1.5 Lto 2 L of the organic solvent, preferably ethylene glycol, 25 mL to 50mL of water and 2.5 mol to 3 mol of the base are added and the mixtureis heated to 140° C. to 200° C., preferably to 155° C. to 185° C., forup to 24 hours, with stirring. All the other steps correspond to thosein the previous embodiment.

Working Up

The amounts given are based on a batch size of 0.05 mol of compound (V).The solvent is conveniently eliminated under reduced pressure, forexample distilled off under a water-jet vacuum, the residue is dilutedwith 30 mL to 100 mL of water, preferably about 5 mL, and stirred into amixture of 100 mL to 150 mL of water (preferably about 125 mL) and 40 mLto 60 mL (preferably about 50 mL) of concentrated hydrochloric acid(approximately 32%), possibly rinsing with water. The telmisartanhydrochloride that crystallizes out is cooled to 10° C. to 25° C. and isstirred for up to 3 hours at this temperature. After the crystals havebeen suction filtered, they are washed with 50 mL to 200 mL of water anddried at 50° C. to 120° C. in a vacuum drying cupboard.

The Examples that follow serve to illustrate the invention and relate toexemplifying embodiments of the methods of synthesis according to theinvention for preparing telmisartan, but without restricting theinvention to their contents.

Example 12-cyano-4′-[2″-n-propyl-4″-methyl-6″-(1′″-methylbenzimidazol-2′″-yl)benzimidazol-1″-ylmethyl]biphenyl

32.24 g of2-n-propyl-4-methyl-6-(1′-methylbenzimidazol-2′-yl)benzimidazole×H₂O isplaced in 100 mL of dimethylacetamide (DMA), and 11.8 g of potassiumtert-butoxide is added batchwise with stirring at approximately 20° C.and then the mixture is stirred for one hour at about 20° C. The mixtureis cooled to 5° C. and then a mixture of 28.6 g of4-bromomethyl-2′-cyanobiphenyl and 95 mL of DMA (dissolved atapproximately 20° C.) is added dropwise over about 30 minutes. Thetemperature of the reaction mixture is maintained at approximately 5°C.-10° C. by cooling with the ice bath. Then it is rinsed with 5 mL ofDMA and stirred for a further 1.5 hours at 5° C. to 10° C.

The solvent is largely distilled off under a water-jet vacuum, duringwhich time the product crystallizes out. The residue is cooled to 60°C., diluted with 230 mL of tert-butylmethylether and stirred for 1 hourwithout any energy input, then cooled to 15° C. to 20° C. and stirredfor another hour at this temperature. The crystals are suction filtered,washed batchwise with 100 mL of tert-butylmethylether, then with 250 mLof water, and then dried in a vacuum drying cupboard at 80° C. Yield:43.3 g (87.5% of theory); melting point: 196° C.-197° C.; HPLC: >99.9%.

Example 22-cyano-4′-[2″-n-propyl-4″-methyl-6″-(1′″-methylbenzimidazol-2′″-yl)benzimidazol-1″-ylmethyl]biphenyl

32.24 g of2-n-propyl-4-methyl-6-(1′-methylbenzimidazol-2′-yl)benzimidazole×H₂O isplaced in 100 mL of DMA, and 6.9 g of potassium hydroxide (powder) isadded batchwise with stirring at approximately 20° C. and then stirredfor one hour at about 20° C. to 25° C. The mixture is cooled to 5° C.and then 28.6 g of 4-bromomethyl-2′-cyanobiphenyl in 95 mL of DMA(dissolved at approximately 20° C.) is added dropwise over approximately30 minutes. The temperature of the reaction mixture is maintained atapproximately 5° C. to 10° C. by cooling with the ice bath. Then it isrinsed with 5 mL of DMA and stirred for a further 1.5 hours at 5° C. to10° C.

The solvent is largely distilled off under a water-jet vacuum, duringwhich time the product crystallizes out. The residue is cooled to 60°C., diluted with 225 mL of tert-butylmethylether, and stirred for 1 hourwithout any energy input, then cooled to 15° C. to 20° C. and stirredfor another hour at this temperature. The crystals are suction filtered,washed batchwise with 100 mL of tert-butylmethylether, then with 250 mLof water, and then dried in a vacuum drying cupboard at 80° C. Yield:40.45 g (81.7% of theory); melting point: 196° C.-197° C.; HPLC: >99.9%.

Example 32-cyano-4′-[2″-n-propyl-4″-methyl-6″-(1′″-methylbenzimidazol-2′″-yl)benzimidazol-1″-ylmethyl]biphenyl

6.9 g of potassium hydroxide (powder) is placed in 50 mL of DMA, stirredfor 15 minutes at 20° C. to 25° C., and then a suspension of 32.24 of2-n-propyl-4-methyl-6-(1′-methylbenzimidazol-2′-yl)benzimidazole×H₂O in50 mL of DMA is metered in at 20° C. to 25° C. After it has all beenadded, the vessels are rinsed with 10 mL of DMA and then stirred foranother hour at 20° C. to 25° C. The mixture is cooled to 5° C. and then28.6 g of 4-bromomethyl-2′-cyanobiphenyl in 95 mL of DMA (dissolved atapproximately 20° C.) is metered in. The temperature of the reactionmixture is maintained at approximately 5° C. to 10° C. by cooling withthe ice bath. Then it is rinsed with 5 mL of DMA and stirred for afurther hour at 5° C. to 10° C.

The solvent is largely distilled off under a water jet vacuum, duringwhich time the product crystallizes out. The residue is cooled to 60°C., diluted with 250 mL of tert-butylmethylether, and stirred for 2hours without any input of energy. The crystals are suction filtered,washed batchwise with 100 mL of tert-butylmethylether, then with 250 mLof water, and then dried in a vacuum drying cupboard at 80° C. Yield:43.37 g (87.5% of theory); melting point: 196° C.-198° C.; HPLC: 99.1%.

Example 42-cyano-4′-[2″-n-propyl-4″-methyl-6″-(1′″-methylbenzimidazol-2′″-yl)benzimidazol-1″-ylmethyl]biphenyl

53.4 g of potassium hydroxide (powder) is placed in 385 mL of DMA andthen a suspension of 248.25 g of2-n-propyl-4-methyl-6-(1′-methylbenzimidazol-2′-yl)benzimidazole×H₂O in385 mL of DMA are metered in at 20° C. to 25° C. After it has all beenadded, the vessels are rinsed with 77 mL of DMA and then stirred foranother hour at 20° C. to 25° C. The mixture is cooled to 5° C. and then209.5 g of 4-bromomethyl-2′-cyanobiphenyl in 731.5 mL of DMA (dissolvedat approximately 20° C.) is metered in. The temperature of the reactionmixture is maintained at approximately 5° C.-10° C. by cooling with theice bath. Then it is rinsed with 38.5 mL of DMA and stirred for afurther hour at 5° C.-10° C.

The solvent is largely distilled off under a water jet vacuum, duringwhich time the product crystallizes out. The residue is cooled to 60°C., diluted with 1925 mL of tert-butylmethylether and stirred for 2hours without any energy input. The crystals are suction filtered,washed batchwise with 770 mL of tert-butylmethylether/DMA (9:1), thenwith 1925 mL of water, and twice with 250 mL of tert-butylmethylether,and then dried at 80° C. in a vacuum drying cupboard. Yield: 322.15 g(84.4% of theory); melting point: 197° C.-198.5° C.; HPLC: 99.6%.

Example 5 Telmisartan×HCl

25 g of2-cyano-4′-[2″-n-propyl-4″-methyl-6″-(1′″-methylbenzimidazol-2′″-yl)benzimidazol-1″-ylmethyl]biphenyl,250 mL of ethylene glycol, 0.9 mL of water. and 24.75 g of causticpotash (>85%) are combined and heated to 160° C. with stirring. Themixture is stirred for 13.5 hours at this temperature.

The solvent is largely distilled off under a water-jet vacuum, theresidue is cooled to 100° C., diluted with 50 mL of water, and stirredinto a mixture of 125 mL of water and 50 mL of concentrated hydrochloricacid (approximately 32%), rinsing with 50 mL of water. The telmisartanhydrochloride that crystallizes out is cooled to 15° C. to 20° C. andstirred for approximately 1 hour at this temperature. After the crystalshave been suction filtered, they are washed with 100 mL of water anddried in a vacuum drying cupboard at 100° C. Yield: 27.3 g (98.2% oftheory); HPLC: 99.9%.

Example 6 Telmisartan×HCl

179 g of2-cyano-4′-[2″-n-propyl-4″-methyl-6″-(1′″-methylbenzimidazol-2′″-yl)benzimidazol-1″-ylmethyl]biphenylis placed in 1611 mL of ethylene glycol, 32.5 mL of water, and 178.7 gof potassium hydroxide (powder) are added and the mixture is heated to150° C. to 160° C. with stirring. The mixture is stirred forapproximately 15 hours at this temperature and then cooled to 100° C.

The solvent is largely distilled off under a water jet vacuum, theresidue is cooled to 100° C., diluted with 358 mL of water, and stirredinto a mixture of 716 mL of water and 358 mL of concentratedhydrochloric acid (approximately 32%), rinsing with 179 mL of water. Thetelmisartan hydrochloride that crystallizes out is stirred for one hourat 60° C., cooled to 15° C. to 20° C. and stirred for approximately 1more hour at this temperature. After the crystals have been suctionfiltered, they are washed with 716 mL of water and dried in a vacuumdrying cupboard at 100° C. Yield: 192.1 g (96.5% of theory); HPLC:>99.9%.

Example 7 Telmisartan

5.51 g of telmisartan×HCl is dissolved in 50 mL of 40% acetic acid whilerefluxing. Then the brown solution is filtered hot through 1.1 g ofcharcoal, washed with 2.5 mL of 40% acetic acid, and 2.5 mL of 4N NaOHis added dropwise to the light brown filtrate with stirring at 80° C. to90° C. The telmisartan crystallizes out, the suspension is diluted with30 mL of water and slowly cooled to ambient temperature. The telmisartanis suction filtered and washed with 50 mL of water. The telmisartan isdried at 80° C. in a vacuum drying cupboard. Yield: 4.80 g (93.3% oftheory).

1-28. (canceled)
 29. A process for preparing telmisartan, comprising:(a) reacting2-n-propyl-4-methyl-6-(1′-methylbenzimidazol-2′-yl)benzimidazole (I)

with a compound of formula (IV)

wherein Z is a leaving group, in a first solvent to obtain a compound2-cyano-4′-[2″-n-propyl-4″-methyl-6″-(1′″-methylbenzimidazol-2′″-yl)-benzimidazol-1″-ylmethyl]biphenyl(V)

and (b) hydrolyzing the nitrile function of compound (V) obtained fromstep (a) into the acid function in a second solvent selected from water,an organic solvent, or a mixture thereof, in the presence of a base attemperatures between 80° C. and 200° C. to obtain telmisartan.
 30. Theprocess according to claim 29, wherein the product of step (a) is workedup before step (b) is performed.
 31. The process according to claim 29,wherein the telmisartan product of step (b) is worked up and convertedinto the hydrochloride.
 32. The process according to claim 29, whereinthe product of step (a) is worked up before step (b) is performed andthe telmisartan product of step (b) is worked up and converted into thehydrochloride.
 33. The process according to claim 29, wherein Z is ahalogen atom or a substituted sulfonyloxy group.
 34. The processaccording to claim 29, wherein Z is a bromine atom.
 35. The processaccording to claim 29, wherein the first solvent is selected frommethylene chloride, diethyl ether, tetrahydrofuran, dioxane,dimethylsulfoxide, dimethylformamide, dimethylacetamide,dimethylformamide/tert-butanol, dimethylacetamide/tert-butanol, toluene,benzene, or a mixture thereof.
 36. The process according to claim 35,wherein step (a) is carried out in the presence of an acid-bindingagent.
 37. The process according to claim 36, wherein the acid-bindingagent is selected from sodium carbonate, potassium carbonate, sodiumhydroxide, potassium hydroxide, sodium methoxide, potassium methoxide,potassium tert-pentoxide, potassium tert-butoxide, potassium n-butoxide,sodium hydride, triethylamine, and pyridine.
 38. The process accordingto claim 29, wherein step (a) is carried out at a temperature between 0°C. and 100° C.
 39. The process according to claim 30, wherein step (a)is carried out at a temperature between 0° C. and 100° C.
 40. Theprocess according to claim 31, wherein step (a) is carried out at atemperature between 0° C. and 100° C.
 41. The process according to claim32, wherein step (a) is carried out at a temperature between 0° C. and100° C.
 42. The process according to claim 29, wherein in step (a) thereaction of the compound (I) with the compound of formula (IV) iscarried out in a first solvent selected from dimethylsulfoxide,dimethylformamide, dimethylacetamide, dimethylformamide/tert-butanol,and dimethylacetamide/tert-butanol in the presence of sodium hydroxide,potassium hydroxide, or potassium tert-butoxide at a temperature between0° C. and 30° C.
 43. The process according to claim 29, wherein afterstep (a) has been carried out, the first solvent is removed and theresidue is treated with a supplementary solvent in which the compound(V) has only limited solubility or is moderately soluble in the heat.44. The process according to claim 43, wherein crystals of the compound(V) are precipitated by cooling the supplementary solvent containing thecompound (V).
 45. The process according to claim 44, wherein thecrystals of the compound (V) are suction filtered.
 46. The processaccording to claim 44, wherein the crystals of the compound (V) aresuction filtered and washed with the supplementary solvent.
 47. Theprocess according to claim 45, wherein the crystals of the compound (V)are dried at elevated temperature.
 48. The process according to claim43, wherein the supplementary solvent is an alcohol, an aromatichydrocarbon, an ether, or water.
 49. The process according to claim 29,wherein the second solvent is methanol, ethanol, n-propanol,isopropanol, tetrahydrofuran, dioxane, ethylene glycol, propyleneglycol,diglyme, dimethylsulfoxide, or diethylene glycol monomethyl ether. 50.The process according to claim 29, wherein the base is selected fromlithium hydroxide, sodium hydroxide, potassium hydroxide, cesiumhydroxide, and calcium hydroxide, or an anhydrides thereof.
 51. Theprocess according to claim 29, wherein the second solvent is ahigh-boiling solvent system selected from ethylene glycol/water andpropyleneglycol/water at temperatures between 140° C. and 200° C. 52.The process according to claim 51, wherein the base is potassiumhydroxide and the temperature is between 155° C. and 185° C.
 53. Theprocess according to claim 29, wherein the telmisartan product of step(b) is worked up by eliminating the second solvent, the residue obtainedis optionally diluted with water and taken up in aqueous hydrochloricacid, and the telmisartan hydrochloride that crystallizes out is cooledif necessary, then suction filtered and optionally dried.
 54. Theprocess according to claim 53, wherein the telmisartan hydrochloride isconverted into the acid form.